New Target Holds Potential for Treatment of Common Anemia

Lexaptepid, an anti-hepcidin therapy, may be the first viable treatment option for patients with anemia of inflammation, according to the results of an experimental study published recently in Blood.

Hepcidin is a principal regulator of iron homeostasis and has therefore been a target for novel therapeutics to treat iron disorders such as anemia. In the small study, use of lexaptepid resulted in clinically relevant hepcidin inhibition in a group of healthy subjects with an inflammation-induced reduction in serum iron.

“We think that a hepcidin-targeted therapy, such as the one investigated in our study, will be a valuable addition to the cur-rent treatment options,” lead study author Lucas van Eijk, MD, of Radboud University Medical Center in Nijmegen, Netherlands, told ASH Clinical News.

Novel Target May Be a Breakthrough for Anemia of Inﬂammation Treatment
During inflammation, inflammatory cytokines stimulate the production of hepcidin by the liver. Hepcidin leads to the internalization and degradation of the cellular iron exporter ferroportin, which is expressed on liver cells and reticuloendothelial cells that store iron and on duodenal cells that absorb dietary iron. When ferroportin is reduced in the cell membrane of those cells, less iron is released into the bloodstream and circulating iron levels decrease — meaning that less iron is available for erythropoiesis in the bone marrow. Inflammation-induced production of hepcidin ultimately leads to iron restriction of the bone marrow, contributing to the development of anemia.

Currently, anemia of inflammation is treated with erythropoietin or intravenous iron supplementation. However, these treatments are not always successful.
In contrast, the hepcidin-targeted therapy lexaptepid should result in the release of iron from reticuloendothelial cells, making it more available for the production of erythrocytes by the bone marrow — helping to ameliorate the condition.

Evaluating Efficacy
Dr. van Eijk and colleagues designed this randomized, double-blind, placebo-controlled trial to evaluate lexaptepid in humans. The study included 24 healthy men who were given 2 ng/kg purified standard reference Escherichia coli (E coli.) endotoxin to induce a controlled state of in-flammation. The subjects were randomly assigned to receive a 15-minute 1.2 mg/kg infusion of placebo or lexaptepid half an hour later.

Subjects in both groups experienced a marked induction of serum iron in the first hours after E coli administration. Thereafter, subjects in the placebo group saw a decline in serum iron as hepcidin concentrations increased. In contrast, those subjects given lexaptepid had a prolonged increase in serum iron concentration, peaking at six hours post-treatment administration.

At nine hours post-administration, serum iron had increased by 15.9 µmol/L from base-line in subjects assigned lexaptepid compared with a decrease in serum iron of 8.3 µmol/L in sub-jects assigned placebo
(p<0.0001).

Interestingly, data showed that 24 hours to 48 hours after treatment serum iron concentrations were lower in subjects treated with lexaptepid than in subjects who received placebo.

“We suspect that the prolonged and strongly elevated serum iron concentrations may have stimulated hepcidin pro-duction to overcome the effect of lexaptepid, eventually resulting in hepcidin-induced hypoferremia,” the researchers wrote.

As a secondary end-point, the researchers also evaluated the effect of lexaptepid on the innate immune response. They observed that all subjects experienced a similar li-popolysaccharide-induced inflammatory response. Flu-like symptoms, body temperature, C-reactive protein, leukocyte counts, and cytokine concentrations were similar be-tween subjects given the investigational drug and those assigned placebo.

“Based on the pharmacology of lexaptepid, we expect patients who are iron-replete but who do not respond well to erythropoietin to respond best to lexaptepid,” Dr. van Eijk said. “This could be patients with chronic kidney disease, patients with cancer-related anemia, or patients with rheumatic disorders.”

According to Dr. van Eijk, lexaptepid could also represent the first specific treatment for iron-refractory iron deficiency anemia (IRIDA), a rare condition caused by genetic mutations leading to inappropriately high hepcidin production.

Now that this study has provided proof of concept, the researchers plan to evaluate the effect of lexaptepid in patients with anemia of inflammation. At the 2014 American Association for Cancer Research Annual Meeting, a poster presentation detailed a pilot study conducted in cancer patients that showed the first activity to increase hemoglobin levels. The drug is also being evaluated in patients on dialysis.